Synthetic studies towards bioactive heterocycles: Platensimycin, sultams, and chromones

Abstract

This thesis is comprised of three parts, linked by the common thread of the synthesis of bioactive heterocycles. PART ONE describes efforts towards the synthesis of the antimicrobial natural product platensimycin 1. Chapter 1 describes the isolation, biological activity and previously published syntheses of 1. Chapter 2 discusses the planned synthetic strategy towards 1 that centred on a tandem Rh(II)-catalysed cyclic carbonyl ylide formation/intramolecular 1,3-dipolar cycloaddition cascade to afford the tetracyclic framework of the platensimycin core. The substrate for this reaction, α-diazoketone 91, was expected to be obtained from the elaboration of a heavily functionalised Diels-Alder adduct 92. Studies towards a simplified model system 105 are described. The dienophile for the Diels-Alder cycloaddition was obtained from a Horner-Wadsworth-Emmons olefination of phosphonate 95 and chiral-pool derived aldehyde 96b. A high-pressure, high temperature Diels-Alder reaction with Danishefsky's diene 93 successfully afforded the desired adduct 101. Functional group manipulation led to advanced intermediate 103; unfortunately, however, installation of the required diazo-moiety proved troublesome and all attempts to effect this transformation ultimately failed. PART TWO describes a study of the proposed cycloaddition reactions of N-alkylsulfonylimines 202. The reaction of these unstable heterocumulenes with 1,3-dipoles is reported sporadically throughout the literature and much of their potential has yet to be explored. Additionally, the heterocyclic adducts proposed to derive from these cycloadditions have unusual and interesting structures that generally have yet to be described in the literature. Thus chapter 5 describes cycloadditions of 202 that were attempted with a variety of 1,3-dipoles including 1,3-dienes, azomethine ylides, donoracceptor cyclopropanes, nitrones, azides, and nitrile oxides. A number of novel and interesting adducts were obtained from the reaction of 202 with 1,3-dienes, nitrones, and nitrile oxides. The conditions required for cycloaddition with donor-acceptor cyclopropanes and azides unfortunately appear to be incompatible with the generation of the unstable dipolarophiles 202. Preliminary antimicrobial screening of these compounds revealed that three of the adducts obtained (340a, 340c, and 340d) exhibit weak bacteriostatic activity against S. aureus. PART THREE describes efforts towards the development of an asymmetric Mukaiyama-Michael addition of silyl enol ethers and/or silyl ketene acetals to chromones. Several C-2-substituted chromanones have been isolated from natural sources and exhibit a wide range of biological activities; yet asymmetric methods for the synthesis of this class of chromanones have only recently been described, and are summarised in chapter 7. Studies towards an asymmetric variant of the Mukaiyama-Michael addition of silyl ketene acetal 550b to chromones based on chiral Cu(II)- bis(oxazoline) Lewis acid technology is described in chapter 8. A number of novel chromanones could be synthesised in variable yields using TMSOTf as the Lewis acid. The asymmetric variant of the conjugate addition, however, was unfortunately unsuccessful, providing chromanones 553b and 554c in low yields and with a total lack of stereoselectivity.